Originally intended for basic neuroscience research, the drugs were ultimately hijacked for illicit recreational use.

Nov 27, 2018

About a decade ago, Clemson University chemist John Huffman started getting calls from law enforcement agencies. Officials from the Drug Enforcement Administration (DEA) and other federal agencies wanted to know more about JWH-18, a synthetic cannabinoid bearing Huffman’s initials that he’d created in the lab in 2004 and described in scientific paper in 2005. The compound was turning up in incense, which, rather than being burnt for its scent, was being smoked and was making people sick.

Huffman’s intent, like other scientists who had generated synthetic cannabinoids over the years, was not to create recreational drugs. It was to study the effects of cannabis in the body and how the cannabinoid system works, as well as to develop molecules to image areas of the brain. “The chemistry to make these things is very simple and very old,” Huffman told The Washington Post in 2015. “You only have three starting materials and only two steps. In a few days, you could make 25 grams, which could be enough to make havoc.”

Chemists studying cannabinoids have become unwitting participants in a growing synthetic cannabinoid drug epidemic with no signs of stopping.

And havoc it’s been. The number of emergency room visits as a result of smoking synthetic cannabinoids, often laced with other drugs, is in the thousands annually, and poison control centers have seen a spike in calls about the compounds in recent years, with nearly 8,000 in 2015. Called K2 or Spice, these synthetic compounds first started sickening Americans in 2008, with illnesses reported in Europe before the drugs reached the US. In 2011, the DEA made it illegal to sell JWH-018 and four related compounds or products that contained them, but that hasn’t kept new synthetic cannabinoids from emerging on the illegal drug market and leading to life-threatening overdoses.

Synthetic cannabinoids are not the first substances concocted in a lab and then hijacked for illicit use. The same thing happened to ecstasy, also called MDMA, and LSD. The difference is that the structure of the cannabinoid system makes it receptive to a diverse set of compounds, setting it up as an easier target for an array of synthetic drugs compared to other systems, says Northeastern University chemical biologist Alexandros Makriyannis. This means chemists studying cannabinoids have become unwitting participants in a growing synthetic cannabinoid drug epidemic with no signs of stopping. Makriyannis himself generated synthetic cannabinoids that served as blueprints for those later sold illegally. “It’s terrible,” he says.

The history of synthetic cannabinoids

The first scientists to study cannabis and create synthetic cannabinoids back in the 1940s had no idea that cannabinoid receptors even existed, nor did they know how marijuana’s phytochemicals interacted with other molecules in the body. Back then, the research seemed a bit more straightforward. Alexander Todd of the University of Manchester and Roger Adams from the Noyes Chemical Laboratory at the University of Illinois at Urbana-Champaign were building analogs to cannabis using organic compounds called terpenoids to try to tease apart the bioactive elements of the drug and the effects they had on the body. These two were the first to produce synthetic molecules that mimicked the effects of cannabis and to show that the compounds they made could have even greater physiological effects than marijuana.

Then, in the 1960s and 1970s, Raphael Mechoulam, a chemist at Hebrew University in Israel, isolated THC, the active ingredient in marijuana. He and others subsequently started to make synthetic compounds based on the structure of THC. The first scientists to study cannabis and create synthetic cannabinoids back in the 1940s had no idea that cannabinoid receptors even existed, nor did they know how marijuana’s phytochemicals interacted with other molecules in the body. Back then, the research seemed a bit more straightforward. Alexander Todd of the University of Manchester and Roger Adams from the Noyes Chemical Laboratory at the University of Illinois at Urbana-Champaign were building analogs to cannabis using organic compounds called terpenoids to try to tease apart the bioactive elements of the drug and the effects they had on the body. These two were the first to produce synthetic molecules that mimicked the effects of cannabis and to show that the compounds they made could have even greater physiological effects than marijuana.

At the same time, scientists at drug companies started to used these researchers’ data and do their own experiments to attempt to make non-opioid–based pain medicine. Among the products created was Nabilone, an FDA-approved drug first developed by Eli Lilly that is designed to reduce brain signals that spur nausea and vomiting, typically in response to cancer treatments such as chemotherapy. Pfizer was also in on the work to make marijuana-based painkillers, which led to what the company called non-classical cannabinoids. Pharmaceutical developers there made many of them, all of which had different effects on the body, depending on slight structural modifications.

The National Institute on Drug Abuse organized a meeting in 1986 of many of the leading cannabinoid researchers at the time to discuss what was known and still unknown about THC and its analogs. Not long after, a few of the scientists at the meeting, including Makriyannis, independently identified the structure of a nerve cell receptor, now called CB1, which responded to THC. It was the first cannabinoid receptor to be documented. A few years later, other researchers identified an additional cannabinoid receptor, CB2. CB2 is fairly rare in the mammalian brain, unless there’s been brain inflammation, neurodegeneration, or cancer, Makriyannis says.

With information on cannabinoid receptors in hand, scientists rushed to create hundreds of synthetic cannabinoids, many by Huffman, to push the system and see how it worked.

From the lab to the street

The efforts to create new synthetic cannabinoids took place mainly in the 1990s and early 2000s—the same time internet access was beginning to become mainstream and researchers started publishing their results online. “When research on synthetic cannabinoids first started, not many people had access to the research journals with the chemical structures of the compounds,” Jenny Wiley, a behavioral pharmacologist who studies cannabinoids at RTI International, tells The Scientist.

As journals went online, she says, chemists looking to make illicit drugs could access not only the chemical compounds of synthetic cannabinoids, but also the data on their potency. In fact, compounds such as Huffman’s might have been hijacked first because he reported both the chemical formula and the potency together in academic journals, Wiley speculates. On the other hand, many of the drug companies’ compounds were patented, and the patents probably did not contain information on the physiological effects of the compounds.

“These rogue chemists were taking the recipes of these synthetic cannabinoids right out of the journals,” says Barbara Carreno, a public affairs officer at the DEA. Wiley suspects the street drugs were first generated in China, but no one knows for sure their precise origin. DEA officials first started to notice the drugs turning up in raids they were doing of shipping containers coming from Europe. There had been reports of use of the drugs in Europe in 2005, but the compounds hadn’t hit the US market until 2008. When the DEA tested the compounds, Huffman’s JWH-18 showed up first, then JWH-250 and JWH-073. “At the time, he was irate that rogue chemists were hijacking his work to make street drugs,” Carreno says.

A public health calamity

There’s not much data on how much money is spent each year on synthetic cannabinoid drug sales, but the DEA does record the top 25 most frequently identified drugs. In 2017, methamphetamine topped the charts with 347,807 drug reports from labs testing compounds in cases of overdoses or drug raids and seizures. Cannabis/THC was second at 344,167 reports. Two synthetic cannabinoids made the top 25 list: FUB-AMB, with 8,108 reports and 5F-ADB with 6,951 reports.

These rogue chemists were taking the recipes of these synthetic cannabinoids right out of the journals.

—Barbara Carreno, DEA

It’s mostly 20- to 30-year-old men, according to the Centers for Disease Control and Prevention, who turn to synthetic cannabinoids as an alternative to marijuana. Some products are “legal” to smoke, if the substances aren’t yet banned by the DEA, and because the ingredients continue to change constantly, they are less likely to be detected in drug screens that may be required for jobs, included in drug addiction treatment plans, and used by law enforcement.

Although the numbers suggest usage is lower for synthetic cannabinoids than for meth or cannabis, the DEA started to become concerned about synthetic cannabinoids as soon as they appeared in the US, mainly because people were getting sick from them. The trouble is that quality control for making synthetic cannabinoids is essentially non-existent, Carreno says. The drug is sprayed onto plant material in large warehouses or sometimes mixed in animal feed troughs, and so the amount of chemical that lands on each piece of plant material is variable, making some batches of Spice of K2 really strong and others not potent at all.

Synthetic cannabinoids have been connected with strings of deaths and devastating overdoses since 2009. In 2018 alone, 56 people overdosed and two died in Chicago; nearly 50 users overdosed in Brooklyn; and more than 100 people got sick in New Haven. In that case, some individuals did test positive for fentanyl, an opioid, in combination with synthetic cannabinoids, which can be a factor in overdosing. But according to a blog published by The Lancet, the main culprit was Fubinaca—a Pfizer-created synthetic cannabinoid–based painkiller that was made illegal in 2014.

The DEA moved to make five synthetic cannabinoids illegal for consumption in 2010, and the federal law passed in 2011. But new ones sprung up to take their places. In later years, some of Makriyannis’s compounds, including AM-2201, turned up on the black market. And since then, rogue chemists keep on tweaking the chemical structure of the compounds to evade restrictions. The DEA continues to test for new substances, but it’s a bit like playing whack-a-mole, Wiley says, with one drug being banned and another popping up on the market.

Makriyannis says he feels some remorse that his compounds escaped the lab and made it to the street. Despite the unanticipated negative effects of his work, he has been undeterred in his studies of the cannabinoid system. In some of his more recent work, he’s been focusing on the CB2 receptor, mainly to show that agonists targeted to it can have pain-relieving effects. Initially, scientists argued that this wasn’t possible, but Makriyannis, in collaboration with Mechoulam and others, demonstrated that activating the receptor reduced pain and also inflammation in animal models. And preclinical studies of Makriyannis’s compound AM-4113, which blocks CB1 receptor activity, suggest it could be a potential treatment for heroine addiction.

“The cannabinoid system is a major biochemical system,” Makriyannis says, explaining that it plays a role in regular brain function and even as part of the immune system. “And there’s a lot left unexplored,” he adds, arguing that researchers have to go on developing drug probes, including synthetic cannabinoids.